Role of Epidermal Growth Factor Receptor Signaling in RAS-Driven Melanoma

Abstract

The identification of essential genetic elements in pathways governing the maintenance of fully established tumors is critical to the development of effective antioncologic agents. Previous studies revealed an essential role for H-RAS^V12G in melanoma maintenance in an inducible transgenic model. Here, we sought to define the molecular basis for RAS-dependent tumor maintenance through determination of the H-RAS^V12G-directed transcriptional program and subsequent functional validation of potential signaling surrogates. The extinction of H-RAS^V12G expression in established tumors was associated with alterations in the expression of proliferative, antiapoptotic, and angiogenic genes, a profile consistent with the observed phenotype of tumor cell proliferative arrest and death and endothelial cell apoptosis during tumor regression. In particular, these melanomas displayed a prominent RAS-dependent regulation of the epidermal growth factor (EGF) family, leading to establishment of an EGF receptor signaling loop. Genetic complementation and interference studies demonstrated that this signaling loop is essential to H-RAS^V12G-directed tumorigenesis. Thus, this inducible tumor model system permits the identification and validation of alternative points of therapeutic intervention without neutralization of the primary genetic lesion.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/.

ACKNOWLEDGMENTS

We thank E. Wagner and W. Cavenee for reagents and R. DePinho for critical review of the manuscript.

N.B. was supported by a Charles A. King Trust postdoctoral award and an DF/HCC SPORE in Skin Cancer Development grant (P50 CA93683). This work was supported by grants from NIH to M.W.B. (K08 CA89124), W.H.W. (P20 CA96470), and L.C. (R01 CA93947; U01 CA84313). L.C. is a V Foundation Scholar.